Biology subjects

Hoffman, M.

Publications and source records attributed to Hoffman, M..

3 recordsLinked to original sources

bioRxiv2018

Subclonal architecture, evolutionary trajectories and patterns of inheritance of germline variants in pediatric glioblastoma

Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. Intratumoral genetic heterogeneity and mode of tumor evolution have not been systematically addressed for this cancer. Whole-genome sequencing of germline-tumor pairs showed that pGBM is characterized by intratumoral genetic heterogeneity and consequent subclonal architecture. We found that pGBM undergoes extreme evolutionary trajectories, with primary and recurrent tumors having different subclonal compositions. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to non-dividing cells. pGBM patients germlines had subclonal structural variants, some of which underwent dynamic frequency fluctuations during tumor evolution. By sequencing germlines of mother-father-patient trios, we found that inheritance of deleterious germline variants from healthy parents cooperate with de novo germline and somatic events to the tumorigenic process. Our studies therefore challenge the current notion that pGBM is a relatively homogeneous molecular entity.

cancer biology↗

bioRxiv2018

Phylogenetic, population genetic, and morphological analyses reveal evidence for one species of Eastern Indigo Snake (Drymarchon couperi)

Accurate species delimitation and description are necessary to guide effective conservation management of imperiled species. The Eastern Indigo Snake (Drymarchon couperi) is a large species in North America that is federally-protected as Threatened under the Endangered Species Act. Recently, two associated studies hypothesized that Drymarchon couperi is two species. Here, we use diverse approaches to test the two-species hypothesis for D. couperi. Our analyses reveal that (1) phylogenetic reconstruction in previous studies was based entirely on variance of mitochondrial DNA sequence data, (2) microsatellite data demonstrate significant population admixture and nuclear gene flow between mitochondrial lineages, and (3) morphological analyses recover a single diagnosable species. Our results are inconsistent with the two-species hypothesis, thus we reject it and formally place Drymarchon kolpobasileus into synonymy with D. couperi. We suggest inconsistent patterns between mitochondrial and nuclear DNA may be driven by high dispersal of males relative to females. We caution against species delimitation exercises when one or few loci are used without evaluation of contemporary gene flow, particularly species with strong sex-biased dispersal (e.g., squamates) and/or when results have implications for ongoing conservation efforts.

zoology↗

bioRxiv2016

A unified encyclopedia of human functional DNA elements through fully automated annotation of 164 human cell types

Semi-automated genome annotation methods such as Segway enable understanding of chromatin activity. Here we present chromatin state annotations of 164 human cell types using 1,615 genomics data sets. To produce these annotations, we developed a fully-automated annotation strategy in which we train separate unsupervised annotation models on each cell type and use a machine learning classifier to automate the state interpretation step. Using these annotations, we developed a measure of the importance of each genomic position called the \"conservation-associated activity score,\" which we use to aggregate information across cell types into a multi-cell type view. The aggregated conservation-associated activity score provides a measure of importance directly attributable to a specific activity in a specific set of cell types. In contrast to evolutionary conservation, this measure is not biased to detect only elements shared with related species. Using the conservation-associated activity score, we combined all our annotations into a single, cell type-agnostic encyclopedia that catalogs all human transcriptional and regulatory elements, enabling easy and intuitive interpretation of the effect of genome variants on phenotype, such as in disease-associated, evolutionarily conserved or positively selected loci. These resources, including cell type-specific annotations, encyclopedia, and a visualization server, are available at http://noble.gs.washington.edu/proj/encyclopedia.\n\nAuthor SummaryGenome annotation algorithms are an effective class of tools for understanding the function of the genome. These algorithms take as input a set of genome-wide measurements about the activity at each base pair in a given tissue, such as where a given protein is binding or how accessible the DNA is to being read by a protein. The genome is then partitioned and each segment is assigned a label such that positions with the same label exhibit similar patterns in the input data. Such annotations are widely used for many applications, such as to understand the mechanism of impact of a given genetic variant. Here we present, to our knowledge, the most comprehensive set of genome annotations created so far, encompassing 164 human cell types and including 1,615 genomics data sets. These comprehensive annotations are made possible by a strategy that automates the previous interpretation step. Furthermore, we present several methodological innovations that make these genome annotations more useful.

genomics↗